Surrogates For Clinical Benefit Research Articles

Abstract IA24: Molecular correlates of T cell-inflamed and non-T cell-inflamed tumors

Abstract IA24: Molecular correlates of T cell-inflamed and non-T cell-inflamed tumors

Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial

PurposePreviously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. Methods and MaterialsClinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. ResultsRectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. ConclusionsThere was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

Patient reported abdominal pain as a surrogate of the clinical benefit of tipifarnib in pancreatic cancer patients.

275 Background: Tumor CXCL12 expression identifies patients who may benefit from tipifarnib therapy. In pancreatic cancer, CXCL12 is known to decrease abdominal pain by inducing the migration of pain suppressing Schwann cells to tumor lesions. Given the association between CXCL12 and pain suppression, we investigated whether the absence of patient reported abdominal pain could be a surrogate of clinical benefit from tipifarnib in pancreatic cancer patients. Methods: We conducted a retrospective analysis of a randomized placebo-controlled trial comparing gemcitabine plus tipifarnib (GT) versus gemcitabine plus placebo (GP) in pancreatic adenocarcinoma patients. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine at standard dosing. Primary study end point was overall survival. Results: 688 patients were enrolled of whom 155 (22.5%) reported no abdominal pain at study entry, 81 received GT and 74 GP. Baseline characteristics were balanced in the subset of patients with no reported abdominal pain (GT,GP): median age (63,59), female gender (35%,43%), ECOG 0-1 (89%,90%), metastatic disease (64%,70%), 6-month weight loss &gt;10% (48%,39%), 6-month jaundice history (51%,45%), and prior Whipple surgery (16%,13%). Subjects receiving GT who did not report abdominal pain at study entry had higher frequency of locally advanced disease (36% vs 24%) and 6-month jaundice (51% vs 38%), and lower frequency of lung (6% vs 14%) and peritoneum (4% vs 13%) metastases than those reporting pain. No differences in survival were observed in the overall study. Median overall survival for GT was 193 vs 182 days for GP. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 305 vs 176 days, HR=0.52, p&lt;0.0001, whereas no significant effect was observed in the control arm: 184 vs 182 days. A trend for better survival with GT was observed in subset of patients with no abdominal pain at study entry (GT,GP): 305 vs 184 days, p=0.058. Conclusions: Absence of abdominal pain may serve as a surrogate of clinical benefit from tipifarnib in pancreatic cancer. (Van Cutsem et al. JCO 2004;22:1430-8; NCT00005648; Trial Sponsor: J&amp;J PRD). Clinical trial information: NCT00005648.

New challenges for comparative effectiveness in oncology: choice of primary end points for randomized clinical trials

Recent advances have led to a steady improvement in cancer treatments. The increasing number of therapeutic options and the corresponding improvement in outcomes pose a number of challenges for comparative effectiveness research in oncology. This review is focused on the choice of primary end points and their interpretation in randomized clinical trials that are designed to inform patients and clinicians on the relative benefits of cancer therapies. We discuss end points that directly measure clinical benefit as well as end points that are thought to be surrogates for clinical benefit. Particular attention is given to the issues associated with the use of overall survival as the primary end point in randomized clinical trials.

Biomarkers in drug development

Due to the increasing understanding of the mechanisms relevant to the genesis of cancer, we are experiencing a transition from diseaseto target-oriented therapy. Thus the challenge of bringing new therapeutics to clinical application and registration now focuses on the molecular target expressed by the malignant cell rather than treatment of the histopathological entity itself. The new concepts, however, bring along major problems for clinical drug development. One major issue is the limited availability of predictive in vitro models on the one hand, and the need to perform early clinical trials usually in heavily pretreated patients with a considerable tumor load on the other. In the new era of cancer treatment, instead of applying the concept of maximum tolerated dose (MTD) as does cytotoxic drug therapy, we must think in terms of the optimal biologically active dose (OBAD) and the maximum tolerated economic cost. Only administration of molecularly targeted drugs at OBAD can demonstrate their optimum therapeutic efficacy. Biomarkers could play important roles in disease diagnosis and in the identification of patient populations that could benefit from targeted therapy. They also serve as markers of drug efficacy and could be used to monitor treatment effectiveness, drug toxicity and development of resistance. Moreover, some biomarkers appear to be surrogates for clinical benefit; as such, they have the potential to serve as endpoints in clinical trials. To use biomarkers to maximum advantage, several scientific hurdles must be surmounted. For example, a need exists to differentiate molecular and therapeutic targets, determine which targets to block to achieve tumor control, overcome resistance mechanisms and identify patients who need treatment and are potential responders.

Arginine Therapy Does Not Benefit Children with Sickle Cell Anemia — Results of the CSCC Clinical Trial Consortium Multi-Institutional Study.

Nitric oxide (NO) is an important inflammatory mediator produced from arginine. NO has a multitude of functions which could impact favorably on vaso-occlusion in sickle cell disease (SCD) including improvement in endothelial dysfunction, increased blood flow and a decrease in antioxidant stress. SCD patients have low NO and arginine levels. In preliminary animal studies using the sickle mouse model, arginine supplementation decreased the mean corpuscular hemoglobin concentration and the percentage of dense cells via a reduction in Gardos channel activity1. In humans with SCD, oral arginine increased NO levels in patients with vaso-occlusive crisis but not when patients were at well. In an attempt to determine if daily oral arginine would result in an increase in NO and other beneficial effects, the CSCC launched a multi-institution, blinded, phase II study of arginine in SCD. Children and adults were treated for three months with one of two doses of arginine (.05g/kg/day or .1 g/kg/day) or placebo. The pediatric and adult cohorts were analyzed separately. For this phase II study, the following laboratory values were chosen as surrogates for clinical benefit: NOx, RBC Gardos channel activity, RBC density, sVCAM, nitrotyrosine, ektacytometry, endothelin-1, and fetal hemoglobin. To determine the impact of arginine on these laboratory measures, patients had 3 baseline assessments in the 4 weeks prior to starting therapy with arginine. An average of these 3 measurements was used to determine change from baseline during therapy with arginine. Laboratory outcomes after one month and three months of therapy with arginine were compared with the average baseline measurement. This report summarizes the results of the pediatric cohort of patients. Fifty-one children were enrolled in the study and 48 completed at least one month of study drug making them evaluable. Arginine levels did not change significantly during treatment in any of the arms. The average percent change from baseline to 3 months on study drug being +18% for placebo, +35% for low dose arginine, and +19% for high dose arginine). None of the three primary outcome variables (NO, Gardos channel activity, RBC density) changed significantly with arginine therapy after one month or after 3 months of arginine. After 3 months of study drug, the average percentage change from baseline in NO was −33% for low dose arginine, +4% for high dose arginine, and +8% for placebo. Gardos channel activity changes were −1% for low dose, +3% for high dose, and +9% for placebo. RBC density changes were +10% for low dose, +11% for high dose, and −6% for placebo. Similarly, none of the other outcome variables changed with treatment at either one or 3 months. There were no significant differences in adverse events between the three treatment groups. Our data indicate that oral arginine therapy does not seem to provide clinical benefit for pediatric patients with SCD based on assessment of these selected laboratory outcomes. It is possible that the doses of arginine used in this study were not sufficient to produce significant changes in the laboratory measures chosen. It is also possible that children, due to less severe arginine deficiency, did not respond as well as adults with SCD.Supported by NHLBI U54HL070587.